This proposal builds on work accomplished during the previous funding period to further our understanding of the basic mechanisms of olfactory transduction and adaptation in human olfactory receptor neurons (ORNs) and extend these studies to examine the basis for olfactory dysfunction associated with aging and neurodegenerative disease (Alzheimer's dementia). Over the past decade, we have learned a great deal about the peripheral receptor and transduction mechanisms responsible for the initial events in odor perception in a wide variety of animal species. Students we have conducted of human olfactory receptor mechanisms reveal that they exhibit features unlike those observed in other species studied in they are more selective and can exhibit an unusual type of calcium response. These funding stress the importance of research with human tissue such as that proposed, in order to fully understand human physiology. The olfactory system is unique as an outpost of the nervous system accessible to biopsy. Studies into the mechanisms underlying the decline in olfactory function associated with age and various neurodegenerative diseases such as Alzheimer's dementia (AD) are of importance both for the potential they provide to identify means of preventing or alleviating this sensory deficit as well as to reveal underlying causes of neuronal dysfunction elsewhere in other parts of the nervous system. Our preliminary studies suggest that ORNs from older subjects and AD patients exhibit functional differences from those of younger subjects and from each other in their selectivity and sensitivity to odorants and pharmacological agents. This proposal comprises electrophysiological and biophysical studies of ORNs freshly isolated from biopsies of the olfactory epithelium. These studies will: elucidate the cellular mechanisms involved in the transduction of (Aims I and II) and adaptation to (Aim III) odorant stimulation, as well as investigating changes that occur in ORN function with age and in AD (Aims III-V). Results will lead to a better understanding of the basis for age- and disease-associated olfactory impairment and provide direct information about changes that may also be occurring elsewhere in the nervous system.